Identification of Potent,Selective Protein Kinase C Inhibitors Based on a Phorbol Skeleton

The elucidation of specific functions of protein kinase C (PKC) subtypes in physiological processes is an important challenge for the future development of new drug targets. Subtype‐selective PKC agonists and antagonists are useful biological tools for this purpose. Most of the currently used PKC modulators elicit their activities through binding to the ATP binding site of PKC, which shares many features with other kinases. PKC modulators that target the PKC regulatory domain are considered to be advantageous in terms of selectivity, because the structure of the regulatory domain is intrinsic to each PKC subtype. In this paper, we describe the identification of new potent and conventional PKC‐selective inhibitors that target the regulatory domain. The inhibitors contain a phorbol skeleton, a naturally occurring potent and selective PKC regulatory domain binder, with a perfluorinated alkyl group and a polyether hydrophilic chain on a terephthaloyl aromatic ring at the C12 position. Both of these substituents are essential for the potent inhibitory activity. Specifically, the binding affinity between PKC and the phorbol ester analogues was improved by an electron‐deficient aromatic ring at C12. This finding cannot be explained by the previously proposed binding model and suggests a new binding mode between phorbol esters and PKC.